Abstract Background: The phase 3 PACIFIC trial established durvalumab (durva) after concurrent chemoradiotherapy (cCRT) as standard of care for unresectable Stage III NSCLC. We report exploratory, post-hoc analyses to assess the impact of smoking status on outcomes in pts from PACIFIC. Methods: PACIFIC was a double-blind trial of pts without disease progression after platinum-based cCRT (≥2 cycles). Pts were randomized 2:1 to receive durva 10 mg/kg or placebo (pbo) intravenously q2w for ≤12 months, stratified by age, sex, and smoking history. Primary endpoints were PFS and OS. Treatment effects (HRs) within subgroups of smokers (current and former) and never smokers were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). Results: Of 713 randomized pts, 64 (9%) were never smokers (Table). Baseline characteristics were broadly well balanced; however, irrespective of study arm, proportionally more never smokers (vs smokers) were female, Asian, and had non-squamous histology. Among never smokers, proportionally more pts in the pbo arm vs durva arm were Stage IIIB (52% vs 40%) and had received induction chemotherapy (33% vs 21%). PFS and OS were improved with durva vs pbo in both smokers and never smokers (Table). The incidence of grade 3/4 AEs was proportionally higher in smokers (vs never smokers) in both the durva (34% vs 23%) and pbo arms (30% vs 14%). In contrast, the incidence of any-grade pneumonitis/radiation pneumonitis was proportionally higher in never smokers (vs smokers) in the durva (56% vs 32% [grade 3/4: 7% vs 3%]) and pbo arms (48% vs 23% [grade 3/4: 5% vs 2%]). SmokersNever SmokersDurvalumab (n=433)Placebo (n=216)Durvalumab(n=43)Placebo(n=21)# of PFS events (%)197 (45.5)140 (64.8)17 (39.5)17 (81.0)PFS HR (95% CI)0.59 (0.47-0.73)0.29 (0.15-0.57)Median PFS (95% CI), mo16.8 (12.3-17.8)6.4 (4.9-8.7)NR (7.2-NE)3.0 (1.8-5.6)12-mo PFS (95% CI), %55.7 (50.6-60.5)37.5 (30.8-44.2)57.8 (40.8-71.5)8.4 (0.6-29.9)18-mo PFS (95% CI), %43.1 (36.2-49.7)28.4 (20.9-36.4)57.8 (40.8-71.5)NR (NE-NE)*# of OS events (%)169 (39.0)103 (47.7)14 (32.6)13 (61.9)OS HR (95% CI)0.72 (0.56-0.92)0.35 (0.16-0.76)Median OS (95% CI), moNR (33.2-NR)29.1 (23.5-NR)34.9 (28.3-NR)18.7 (12.5-31.0)12-mo OS (95% CI), %82.8 (78.9-86.1)75.3 (68.9-80.6)86.0 (71.6-93.5)75.4 (50.6-89.0)24-mo OS (95% CI), %65.5 (60.7-69.8)56.7 (49.7-63.2)74.1 (58.0-84.7)43.1 (21.1-63.4)*Kaplan-Meier undefined; no patients at risk at 18 mo.PFS was assessed by blinded independent central review (RECIST v1.1).Median follow up for PFS = 14.5 mo (DCO for the primary analysis of PFS: 13 Feb 2017).Median follow up for OS = 25.2 mo (DCO for the primary analysis of OS: 22 Mar 2018).CI, confidence interval; DCO, data cutoff; HR, hazard ratio; mo, months; NR, not reached; NE, not estimable; OS, overall survival; PFS, progression-free survival. Conclusions: Consistent with the ITT population, durva improved PFS and OS in both smokers and never smokers with unresectable Stage III NSCLC who had received prior cCRT. The small size of the never smokers subgroup and imbalances in baseline characteristics preclude robust conclusions regarding inter-subgroup differences in clinical outcomes. Citation Format: David Planchard, Mustafa Özgüroğlu, Davey Daniel, Augusto Villegas, David Vicente, Shuji Murakami, Rina Hui, Corinne Faivre-Finn, Luis Paz-Ares, Yi-Long Wu, Euan Macpherson, Michael Newton, Phillip Dennis, Scott J. Antonia. Impact of smoking on outcomes with durvalumab following chemoradiotherapy in unresectable Stage III NSCLC (PACIFIC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT213.

Many oncology studies incorporate a blinded independent central review (BICR) to make an assessment of the integrity of the primary endpoint, progression free survival. Recently, it has been suggested that, in order to assess the potential for bias amongst investigators, a BICR amongst only a sample of patients could be performed; if evidence of bias is detected, according to a predefined threshold, the BICR is then assessed in all patients, otherwise, it is concluded that the sample was sufficient to rule out meaningful levels of bias. In this paper, we present an approach that adapts a method originally created for defining futility bounds in group sequential designs. The hazard ratio ratio, the ratio of the hazard ratio (HR) for the treatment effect estimated from the BICR to the corresponding HR for the investigator assessments, is used as the metric to define bias. The approach is simple to implement and ensures a high probability that a substantial true bias will be detected. In the absence of bias, there is a high probability of accepting the accuracy of local evaluations based on the sample, in which case an expensive BICR of all patients is avoided. The properties of the approach are demonstrated by retrospective application to a completed Phase III trial in colorectal cancer. The same approach could easily be adapted for other disease settings, and for test statistics other than the hazard ratio. Copyright © 2015 John Wiley & Sons, Ltd.

5505 Background: Previously, we reported that maintenance treatment with the oral PARP inhibitor olaparib (400 mg bid) led to a significant PFS improvement vs placebo in patients (pts) with platinum-sensitive relapsed SOC (Ledermann et al NEJM2012). A preplanned subgroup analysis from this randomized, double-blind Phase II trial (NCT00753545) suggested that olaparib may lead to a greater PFS, and an OS, benefit in pts with a known germline BRCAm (gBRCAm). Since gBRCA wild-type (gBRCAwt) pts may develop somatic tumor (t)BRCAm, efficacy analyses were performed for all pts with BRCAm. Methods: gBRCAm status was determined retrospectively for all consenting pts (n = 166) using blood samples taken before randomization. tBRCAm status was determined from archival tumor samples of 196 pts. We analyzed PFS/OS by gBRCAm and total BRCAm status. Preliminary data are reported. Results: gBRCA status was known for 218/265 pts (gBRCAm, 96; gBRCAwt, 122). Including tBRCAm, 136 pts had a BRCAm (BRCAwt, 116). gBRCAm pts had the greatest PFS benefit with olaparib maintenance vs placebo (median: 11.2 vs 4.1 months [m]; HR, 0.17; 95% CI 0.09-0.32; P<0.001) and a significant QoL improvement, as measured with Trial Outcome Index (OR, 4.08; 95% CI 1.11-19.85; p = 0.03). The PFS benefit was consistent when tBRCAm pts were included (median: 11.2 vs 4.3 m; HR, 0.19; 95% CI 0.11-0.32; p <0.0001). In an interim analysis of OS (58% maturity), a comparison of olaparib vs placebo in the overall population led to a HR of 0.88 (95% CI 0.64-1.21) with medians of 29.8 vs 27.8 m, respectively. Although HRs from the gBRCAm and gBRCAwt subgroups were similar (0.85 and 0.84, respectively), 13/37 gBRCAm placebo pts received a subsequent PARP inhibitor, confounding the OS data in this subgroup. The analysis of all BRCAm pts was less confounded and resulted in an OS HR of 0.74 (95% CI 0.46-1.19; median: 34.9 vs 31.9 m). 19 pts have received olaparib for >3 years. Olaparib tolerability was similar in BRCAm pts and the overall population. Conclusions: Olaparib maintenance treatment led to the greatest clinical benefit in pts with a BRCAm. These compelling data warrant confirmation in phase III trials. Clinical trial information: NCT00753545.

BACKGROUND Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). CONCLUSIONS Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

Background The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. Patients and methods Patients aged ≥18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m2/day × 3 days or 1.0 mg/m2/day × 3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan. Results Twenty-one patients were enrolled and 19 received treatment. Dose-limiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m2/day × 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting. Conclusions Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD.

BackgroundOlaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer.MethodsIn this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included …

5003 Background: Olaparib (AZD2281) is an oral PARP inhibitor that has shown antitumor activity in patients (pts) with high-grade serous ovarian cancer (SOC) with and without BRCA1 or BRCA2 mutations. This randomized, double-blind, multicenter, placebo-controlled Phase II study evaluated maintenance treatment with olaparib in pts with high-grade PSR SOC (clinicaltrials.gov; NCT00753545). Methods: Pts with PSR SOC who had received ≥2 previous platinum regimens and were in a maintained partial or complete response following their last platinum-containing regimen were randomized to oral olaparib 400 mg bid or placebo. The primary endpoint was progression-free survival (PFS) by RECIST. Secondary endpoints included time to progression (TTP) by CA-125 (GCIG criteria) or RECIST, overall survival (OS) and safety. Results: 265 pts were randomized (136 to olaparib and 129 to placebo). Demographics and baseline characteristics were generally well balanced. At data cut-off there were 153 (58%) progression events. PFS by RECIST was significantly longer in the olaparib than the placebo group (HR, 0.35; 95% CI 0.25–0.49; P<0.00001; median 8.4 vs 4.8 months). TTP by CA-125 or RECIST was also significantly longer in the olaparib than the placebo group (HR, 0.35; 95% CI 0.25–0.47; P<0.00001; median 8.3 vs 3.7 months). At data cut-off OS data were too immature for analysis. 68 (50%) and 21 (16%) remain on olaparib or placebo, respectively. AEs more commonly reported on olaparib than placebo (by >10%) were nausea (68% vs 35%), fatigue (49% vs 38%), vomiting (32% vs 14%) and anemia (17% vs 5%); the majority of AEs were CTCAE grade 1 or 2. The most frequently reported CTCAE grade ≥3 events were fatigue (9 pts) and anemia (7 pts) for olaparib, and abdominal pain and fatigue (4 pts each) for placebo. 3 (2.2%) pts on olaparib and 1 (0.8%) on placebo had AEs that led to treatment discontinuation. 31 pts (23%) in the olaparib group and 9 (7%) in the placebo group had both dose reductions and interruptions. Conclusions: In pts with PSR SOC, maintenance treatment with olaparib 400 mg bid provided a significant improvement in PFS. Olaparib was well tolerated, and toxicities were consistent with previous studies.

Background Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer.Methods In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included in the primary efficacy analysis. This trial is registered at ClinicalTrials.gov, number NCT00679783.Findings 91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22-64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14-38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%]).Interpretation Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed.

3002 Background: Olaparib is a PARP inhibitor (PARPi) which has reported encouraging response data in BRCA mutation carriers. We have completed a phase II translational study evaluating tumor response with serial tumor biopsies to determine markers of response. Methods: Eligible women with advanced breast (BC) or ovarian cancer (OC) were enrolled in 4 cohorts. A Simon 2 stage design was used for 2 cohorts of BRCA mutation negative or unknown patients (pts) with either high grade serous OC (Arm A) or triple negative BC (Arm B). Two other cohorts are reference groups with recurrent OC (Arm C) or BC (Arm D) with identified BRCA mutations. All (pts) had tumor biopsies prior to treatment, after 2 cycles and at progression to assess PARPi activity, loss of heterozygosity (LOH), mutational changes, BRCA1/2 expression, and markers of response including deep sequencing. CT/MRI assessments were done prior to treatment and every 2 cycles. Selected pts had PET scans. Pts were treated with single agent olaparib 400 mg bid on a continuous basis in 4 week cycles. Results: 91 evaluable pts were enrolled. Arm A enrolled 55 pts after evidence of response(s) in the first 15 pts. Arm B did not meet continuation criteria and closed at 15 pts. Arms C and D enrolled predetermined numbers of 10 and 11 pts. Preliminary results show 3 partial responses in Arm C with 6 pts in Arms C and D continuing on treatment at this time. In arm A, 20 of 55 measurable pts remain on treatment with 22+ pts receiving ≥6 cycles of olaparib. Confirmed radiological PRs have been observed in 8 pts with GCIG CA125 response criteria in 14 pts and 142 biopsies collected overall. Conclusions: This is the first trial demonstrating significant evidence of single agent activity of olaparib in women with high grade serous OC. Updated translational study data and response data in BRCA+ and BRCA− tumors will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca

PURPOSE:To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the approved dose) with the aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor-positive breast cancer in postmenopausal women.PATIENTS AND METHODS:FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study of a fulvestrant high-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable disease for > or = 24 weeks. The primary analysis was performed 6 months after the last patient was randomly assigned.RESULTS:CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103), 72.5% v 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386). Objective response rate (ORR) was also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Time to progression (TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for fulvestrant HD v 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39 to 1.00; P = .0496). Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of prespecified adverse events.CONCLUSION:First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.